2-carboalkoxy-3-keto-4-acylamido-tetrahydrothiophene



UNITED STATES PATENT OFFICE 2- CARBOALKOXY-3-KETO-4-ACYLAMIDO- TETRAHYDROTHIOPHENE Stanton A. Harris, Westfield; N. J., assignor to Merck & Co.,vInc., Rahway, N. J., a corporation of New Jersey v No Drawing. Application September 16, 1944, Serial No. 554,450

15 Claims. (Cl. 260-329) This invention is concerned generally with novel (7) chemical compounds and processes of preparing the same; more particularly it relates to novel {(RCOMO compounds useful as intermediates in synthesis of the growth-promoting factor, biotin. 5 5 R00 R00 S Biotin is known to be one of the isomers of the NH 1 m 7 NH NH chemical compound 2- (4 -carb oxy-butyl) -3 :4 I

ureldo-tetrahydr0th1ophene, having the empirl- [I cal formula G1uH1sO3N2S, and the structural for- 5 =OH(CH')3OO1R CHPFC-(Cmficom mula: 1) (9b) IE: catalyst H RCO R00 H2 --s--oHoH2oHoHloHlo02H NH IIIH It is now found that this compound can be W synthesized by reactions indicated as follows: om-s-omonmoom 10) NH: N Hz l 011-, then 11+ oH-o0 H CH-CO H M x'cmcom N NH Hz-SH OHzS--CH2G 02H CH CH (1) (2) tm-a-momhooln 11) lRO 0x I cox, m z'o Roe NH HN--(l'--NH (tn-002R (JR-002B H a 4.

ROH f 1 ours-onto 01R m s omoom HrsiHwHmCofi (12) (4) (a) In the above formulae, R represents an alkyl, M aryl or arylalkyl group; X, a halogen; and M an l alkali metal or an alkaline earth metal.

RC0 RC0 The reactions above indicated are conducted as follows: 2-amino-3-mercapto-propanoic acid Y (1) and chloroethanoic acid are condensed in oH----o oH-- d an alkaline aqueous solution to form 2-amino 3- 1 H+,Hz0 I t 40 carboxy-methylmercapto-propanoic acid (2'); CHr-S CO2R heat (mks-CH2 which is then treated with an acylating agent,

M suchas an acyl halide, in anaqueou's alkaline t t (6) solution to yield 2-acylamido-3-carboxymethy1- mercapto-propanoic acid (3). This product is lo=e em =com esterified using a mineral acid catalyst, to pro II] a a duce the diester 4) of the acid (3), and the at R90 3 ester is treated with alkali metal alcoholate or H M NH 0 an alkaline earth metal alcoholate to yield the NH NO J g FZQ a g Z-aIkali metal or the 2-a1kaline earth metal de- (L: a t 1 rivativeofan ester of Z-caiboky-S-keto-4-acy1- =Q B fiesrcmcmmom amideaarahyarotmbphene (5). This. cem- Ii pound, when heated with a dilute mineral acid, is hydrolyzed and decar'ooxylatcd to produce 3 keto 4 acylamido tetrahydrothiophene (6) which, when reacted with a-carhoxy butanal ester in a lower aliphatic alcohol reactio medium containing pipericiine and a lower aliphatic carboxylic acid, produes 2(4-carboal *oi ;ybutylidene) 3-l:.eto4acylainido-tetrahydrothiophene (7). This product, whenreacted with hydroxylamine yields an ester of the corresponding oxime, 2-(4-carbo::y-butylidene "3- isonitrosol-acylamido tetrah: niophene (8) which upon treatment with a mixture of zinc, a lower aliphatic acid and a lower aliphatic acid anhydride, produces an equilibrium mixture of 2- (4'- carboxy butylidene).- 3 4- di(acylamido) m tetrahydrothiophene ester (9d) and. 2-(4-car-. boxy-butyl -3 :4-di (acylamido) 4 :-dihydrothio phene ester (9b). This equilibrium mixture, or if preferred, one of the equilibrants, is then treated with hydrogen in the presence of a hydrogenation catalyst to yield 2-(4'-carboxybuty1l3:4- di (acylamido) -tetrahydrothiophene ester (10) When this last mentioned compound is treated with an acueous alkaline solution, hydrolysis of the acyl groups occurs, yielding upon acidification, 2- (4-carboxybutyl) 3 :4- diamino tetra hydrothiophene (11 which, when reacted with a carbonyl halide, produces the compound 2A4- carboXy-butyl) 3 4-ureidotetrahydrothiophene. This product is obtained as a mixture of stereoisorners, one of which is racemic biotin, from which upon resolution, is obtained the dextrorotatory isomer, biotin.

The present invention is concerned with. intermediate 5 above, the ketone and the 2-alkali metal and 2-alkaline earth metal derivatives simple keto-addition products are representative of this class of derivatives.

The starting material utilized in practice of the present invention, 2-acylamido3-carboxymethylmercapto-propanoic diester, can be prepared as described in the applications, Serial Nos. 554,449; and 554,458, now Patent No. 2,466,232, concurrently filed by the present inventor.

The following example illustrates a method of carrying out the present invention, but it is to be understood that this example is given by way of illustration and not of limitation.

Example o6H5o=o ofinsc=o NH NaOCHa NH 0 I 1 Hc cooom onion H(|3Cl/Na oHr-s-omoooom H2o-so o 0 0 CH3 To a solution of about 770 g. of the dimethyl ester of 2-benzamido-3-carboxymethylmercaptopropanoic acid in approximately 500 cc. of methanol, about 57 g. of sodium dissolved in 100 cc. of methanol is added. The 2-sodium derivative of 2-carbomethoxy 3 keto-4-benzamido-tetrahydrothiophene separates from the reaction mix-- ture and is removed by filtration, washed with methanol; and dried. When heated the produc decomposes without melting.

In a similar manner other Z-acylamido-B-carb' oxymethylmercapto propanoic diesters when treated with sodium alcoholate or another alkali of the ketone 2-carbalkoxy-3-keto-4-acylamidotetrahydrothiophene, represented by the formula:

. M wherein R is an acyl groupfli is hydrogen or an metal or alkaline earth metal alcoholate yield corresponding 2-metal derivatives of 2-carbalkoxy-3-keto-4-acylamido-tetrahydrothiophene.

When treated with a dilute mineral acid, the 2-sodium derivative of 2-carbomethoXy-3-keto-4- benzamido-tetrahydrothiophene yields the corresponding free ester, 2-carbomethoxy-3-keto-4- benzamidotetrahydrothiophene. a The correspondingoximino compound of..the

I 3-keto free ester is prepared by mixing aboutBO-g.

alkyl, aryl or arylalkyl group, M is hydrogen, an

alkali metal o an alkaline earth metal; and simple derivatives thereof involving the 8-keto functional group. The above intermediate compounds are converted intothe vitamin biotin by the process steps above indicated as described in detail in concurrently filed applications, Serial Nos. 554,451, nowPatent No. 2508,457; 554,452, new Patent No. 2,452,653; 554,453, now Patent No. 2 ,460, 24; 554,454, now Patent No. 2,459,817;

554,455, now Patent No. 2,487,050j 554,456, now

abandonedyand 554,457, now abandoned.

. According to the present invention, these cornpounds are obtained by treating a 2-acylamido- 3-carboxymethylmercaptopropanoic diester, pref erably in an aliphatic alcoholic reaction medium,

, of the 2-sodium derivative of' 2'-c arbom'ethoxy,3-

keto-4-benzamido tetrahydrothiophene with a chemically equivalent quantity of hydroxylamine hydrochloride in about 75 cc. of pyridine and allowing the mixture to stand for about 36 hours. Water is then added, the mixture is extracted with ether; the ether extract is washed with aque: ous acid, dried, and concentrated to obtain an oil which is dissolved in methanol, ether is added,

3 and a precipitate of 2-carbomethoxy3-oximidowith an alkali metal alcoholate or an alkaline earth metal alcoholate which causes formation of a heterocyclic nucleus. Upon treating the metal derivative thus obtained with dilute acid at room temperature (30 C.) or below, the corresponding free ester can be obtained, Z-carballrtoward a keto g roup results in form ationof simple derivatives involving the 3-keto functional group.

The'oxime, semi-carbazone, 'arylhydrazones and 4-benzamino-tetrahydrothiophene (M. P. 157 C.) is obtained, which is separated byfiltration. After removing this product crystalsjof an isomeric form of the oxime (M. P. 132-l33 C.)

' are obtained from the filtrate.

The phenylhydrazone of the 3-keto free ester is prepared by mixing about 3 g. of the 2-sodium derivative of 2-carbomethoxy-3-keto-4-benzamido-tetrahydrothiophene in an aqueous solution with an aqueous solution of 1.44 g. of phenylhydrazine hydrochloride. A gummy mass is obtained which is treated with methanol causing evolution of heat, and the separation of the phenylhydrazone :of 2-carbomethoxy-3-l;eto-4- benzamido tetrahydrothiophene (M. P. 155- 156 C.) which can be removed and purified by conventional operations In like manner the Z-Sodium or other 2-metal derivatives can be-re'acted-wi-th other reagents capable of; combining with ketones to .produce corresponding derivatives. For example, mem

51. bers of ilthisnclass'of compounds "can be reacted with 'serribcarbazide to form the corresponding semi-carbazone, or with nitrophenylhydrazine to yield the corresponding nitsophenylhydrazine, etc.

Compounds having other acylamido groups in place of the benzamido group present in the specific compound used in the process of the above example enter into analogous reactions with the reagents mentioned. Corresponding esters other than the methyl ester also react with these reagents in the manner above described.

Modifications may be made in carrying out the present invention without departing from the spirit and scope thereof and the invention is to be limited only by the appended claims.

What is claimed is:

1. A compound of the formula:

R1|\IH (l 1:0 mps-01100211 wherein R is an acyl group and R isna'n alkyl radical.

2. A compound of the formula:

ni n CH(1):O (BET-peach wherein Hfisan acyl group, R is an alkyl radical and Mis an alkali metal. 3. A compound of theformula:

wherein R is an acyl group and R is an alkyl radical.

4. A compound of the formula:

CsH5C 0 NH lH-C:O duke-(50020113 5. A compound of the formula:

C6H5C 0 NH JH-C:O

6. A compound selected from the class consisting of the ketone represented by the formula:

wherein R is an acyl group, R is a radical selected from the class which consists of alkyl, aryl and arylalkyl radicals, and M is a radical selected from the class which consists of hydrogen and alkali metals, and the oxime, semicarbazone, and aryl-hydrazones of said ketone.

7. The process which comprises treating a compound represented by the formula:

c whereinR. is 'an acyl group. and 'R' is a radical selected from the class which consists of alkyl; aryl and arylalkyl radicals, with a compound having the formula: R"OM, wherein R" is a lower alkyl radical, and M'is an alkali metal, to produce a compound of the formula:

wherein R, R and M have the significance abovedefined.

8. The process which comprises treating a compound represented 'by the formula:

wherein R is an acyl group and R is. an alkyl radical, with an alkali metal alcoholate to produce a compound of the formula:

wherein R and R have the significance abovedefined.

10. The process which comprises treating a compound represented by the formula:

cameo IIIH with sodium methylate to produce a compound of the formula:

11. The process which comprises treating a compound represented by the formula:

wherein R is an acyl group, R is a radical selected from the class which consists of alkyl, aryl and arylalkyl radicals, and M is an alkali metal, with dilute acid at a temperature below 7 8 about 30 C., to produce a compound having the With'idilllt mineral acid at a temperature below formula: about 30 6., to produce a compound of the I RNH formula: V

(3:0 5 I 0611500 ours-(moody 1 wherein R and R have the significance above- Hflcio defined. nr-s-ofloozcns 12. The process which comprises treating a A tetrahydrothiophene compound repre compound represented by the formula: 10 sented by therfonowing formula:

RNH COOR CH-C:O OH C=O (EHrS-ifCOzR' S 15 Na \inz-on wherein R is an acyl group and R is an alkyl 5 radical, with dilute acid at a temperature below 1 about 30 C., to produce a compound having the formula: 20 A RNH where the R is alower alkyl group and A is selected from the group consisting of alkyl, aral- I I kyl and aryl groups. CH2*S CH CO2R 15. The compound represented by the formula wherein R and R have the significance above- 5 of claim 14 where 1 a pheny1gr0up defined- STANTON A. HARRIS.

13. The process which comprises treating a compound represented by the formula: REFERENCES CITED CBHA JO The following references are of record in the NH file of this patent:

oH--o:o UNITED STATES PATENTS r znr-s-o-c 02cm Number Name Date l 2,472,433 Moore et a1 June 7, 1949 

1. COMPOUND OF THE FORMULA: 